GENETIC ANALYSES OF GENES IN PRESENILIN RELATED PATHWAYS

早老素相关通路基因的遗传分析

• 批准号: 7483171
• 负责人: RUDOLPH Emile TANZI
• 金额: $ 47.11万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483171
• 关键词: 19q; Affect; Age; Allosteric Regulation; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apolipoprotein E; Biological; Candidate Disease Gene; Catalysis; Categories; Chromosomes; Chromosomes, Human, Pair 19; Complex; Data; Evaluation; Family; Follow-Up Studies; Funding; Generations; Genes; Genetic; Genetic Transcription; Genome; Genomics; Haplotypes; Individual; Laboratories; Ligand Binding; Linkage Disequilibrium Mapping; Logistic Regressions; Methods; National Institute of Mental Health; Pathogenesis; Pathway interactions; Positioning Attribute; Post-Translational Protein Processing; Protein C; Proteins; RNA Splicing; Relative (related person); Resolution; Resources; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Survival Analysis; Testing; base; disorder risk; gamma secretase; genetic analysis; genetic linkage; genetic linkage analysis; novel; presenilin; secretase; signal peptide peptidase

In Project 2, we have shifted our focus to genetic analyses of positional candidate genes encoding proteins implicated in presenilin-related pathways. Over the past decade, our group has led the ascertainment, evaluation, and comprehensive genetic analyses of the NIMH Genetics Initiative Alzheimer's disease (AD) sample. This set of AD families, which currently includes 1527 individuals in 457 families, is the largest uniformly ascertained and evaluated sample ever assembled for the study of AD genetics. In separately funded studies, our laboratory recently completed the genetic analyses and preliminary follow-up studies of a comprehensive high-resolution genome screen for novel AD genes. The genome screen revealed that in addition to the expected highly significant linkage peak on chromosome 19q (APOE locus), several regions demonstrate evidence of 'suggestive' linkage to AD. In separately funded studies, we are further refining these linkage regions using additional markers. The immense data emanating from this screen constitute a powerful resource for research efforts aimed at identifying novel AD genes. To identify novel AD genes, we propose a positional candidate approach in which we test biologically compelling candidate genes from our AD genetic linkage peaks using family-based association, augmented by linkage disequilibrium mapping. Clusters of tightly spaced single nucleotide polymorphisms (SNPs) in positional candidate genes encoding proteins that are biologically implicated in presenilin-related pathways will be tested for association with AD. These genes have been divided into six categories: a. presenilin interactors, b. PS/gamma-secretase substrates, c. PS/gamma-secretase complex components and proteins that affect PS/gamma-secretase activity/Abeta generation, d. amyloid precursor protein (APP) C-terminus/APP intracellular domain (AICD) interactors, e. AICD transcriptional targets, and f. presenilin-like signal peptide peptidases. Testing of these genes will be prioritized according to their genomic position relative to the best-confirmed AD genetic linkage peaks, and their biological relevance to AD pathogenesis. Candidate genes for which positive signals are successfully found in the NIMH sample will be tested in an independent sample, the Consortium on Alzheimer's Genetics (CAG) sample. SNPs found to be strongly associated with AD in these samples will be phenotypically and functionally characterized including collaborative analyses with the six other PPG laboratories.

在项目2中，我们已经将我们的重点转移到位置候选基因编码蛋白质的遗传分析，涉及早老相关途径。在过去的十年中，我们的团队领导了NIMH遗传学倡议阿尔茨海默病（AD）样本的确定，评估和全面的遗传分析。这组AD家族，目前包括457个家族中的1527个个体，是有史以来为AD遗传学研究而收集的最大的统一确定和评估样本。在独立资助的研究中，我们的实验室最近完成了一项遗传分析和初步随访研究， 全面的高分辨率基因组筛选新的AD基因。基因组筛选显示，除了染色体19 q（APOE基因座）上预期的高度显著的连锁峰外，还有几个区域显示出与AD“暗示性”连锁的证据。在单独资助的研究中，我们正在使用其他标记进一步完善这些连锁区域。从这个屏幕发出的巨大数据构成了一个强大的资源，旨在确定新的AD基因的研究工作。为了识别新的AD基因，我们提出了一个定位的基因。 候选人的方法，其中我们测试生物学上令人信服的候选基因，从我们的AD遗传连锁峰使用基于家庭的关联，增加了连锁不平衡映射。将检测编码与早老蛋白相关通路有生物学关联的蛋白质的位置候选基因中紧密间隔的单核苷酸多态性（SNP）簇与AD的相关性。这些基因被分为六类：a.早老素相互作用物，B. PS/γ-分泌酶底物，c. PS/γ-分泌酶复合物组分和影响PS/γ-分泌酶活性/Abeta产生的蛋白质，d.淀粉样前体蛋白（APP）C末端/APP胞内结构域（AICD）相互作用物，e. AICD转录靶标，和f.早老素样信号肽肽酶。这些基因的检测将根据其相对于最佳确认的AD遗传连锁峰的基因组位置及其与AD发病机制的生物学相关性进行优先排序。在NIMH样本中成功发现阳性信号的候选基因将在独立的 样本，阿尔茨海默氏症遗传学联盟（CAG）样本。在这些样本中发现与AD密切相关的SNP将进行表型和功能表征，包括与其他六个PPG实验室的合作分析。